The present invention relates to novel methods for preventing, treating, or reducing the severity of diseases and conditions mediated by β-adrenergic receptors, particularly pulmonary airway diseases. In particular, it provides for methods and compositions for treating pulmonary airway diseases by long-term administration of β-adrenergic inverse agonist drugs, either alone or in combination with other drugs, such as β2-agonists, steroids, leukotriene modifiers, anticholinergics, methylxanthines, phosphodiesterase-4 inhibitors, or anti-IgE antibodies.
Many diseases and conditions are mediated by β-adrenergic receptors. In particular, these receptors are involved in many pulmonary airway diseases. Pulmonary airway diseases are characterized by reduced pulmonary function and airway flow. These symptoms are often due to secretion of mucus or tissue damage. These diseases include allergic rhinitis (“hay fever”), asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), Churg-Strauss syndrome, bronchitis, bronchiectasis, and emphysema. These diseases are serious and are responsible for significant mortality and morbidity.
COPD patients have obstructed airflow in the lungs. There are a number of ways that patients develop COPD. However, the hallmark of the disorder is dyspnea, or breathlessness. COPD is frequently associated with long-term cigarette smoking and can develop as the result of untreated allergic conditions. The aging process can also cause the bronchi and bronchioles to lose their elasticity.
Churg-Strauss syndrome is an inflammatory disease in which patients exhibit asthmatic symptoms such as airway hyperreactivity. Inflammation of pulmonary airways occurs, compromising pulmonary function.
In bronchitis, airway function is compromised due to hypersecretion of mucus, initially due to irritants. Bronchitis can be the result of infection or allergic reaction. With chronic bronchitis, coughing is persistent but may no longer be sufficient to clear airways, leading to airflow obstruction. Chronic bronchitis affects the bronchial tubes.
Bronchiectasis results from infection in the lungs, leading to irreversible airway damage. Patients often complain of persistent cough and expectorate a foul-smelling sputum. The consequences of the infection, in conjunction with the secretions, contributes to airway obstruction despite the fact that bronchi and bronchioles can be exceptionally dilated.
Patients with emphysema have reduced pulmonary function due to destructive damage of the walls of lung alveoli. Often, patients are long-time smokers and have elevated levels of inflammatory cells, such as neutrophils and macrophages, in the lungs; other pathophysiologic processes are at work as well. The smoke is believed to activate lung neutrophils to release elastase, a damaging proteolytic enzyme. Other environmental irritants can also be involved in emphysema.
Asthma alone is a chronic problem for 20 million American patients. The rate of occurrence of asthma has been increasing rapidly in the United States, particularly in urban areas, and particularly in children. The cause of this increase is not known, but exposure to environmental pollutants is suspected. The age-adjusted mortality rate for asthma in the United States increased 55.6% between 1979 and 1998 (American Lung Association's Epidemiology and Statistics Unit, Best Practices and Program Services. Trends in Asthma Morbidity and Mortality, 2002). Persons suffering from asthma are often sensitive to allergens, such as household dust, animal dander, and pollen (allergic asthma). However, intrinsic asthma can be triggered in a patient by emotional distress or panic, as well as by factors such as exposure to cold or exercise, or by administration of certain medications such as aspirin. In asthma, patients exhibit airway hyperresponsiveness to these provocations. These trigger immune system cells to release histamines, IgE molecules, cytokines, or chemokines. Airway smooth muscle responds acutely to these provocations, resulting in bronchial constriction. Additionally, the airway becomes damaged and inflamed, and mucus is secreted, further limiting airway flow. Asthma attacks are characterized by shortness of breath, caused by contraction of the smaller bronchi and bronchioles, chest tightness, coughing, and wheezing. The attacks can be mild, moderate, or severe.
Patients with these airway disorders may have airway spasms, further reducing airflow through the pulmonary tree. During an attack, a patient's airway is constricted, leading to difficulty breathing. Airway smooth muscle is responsible for the bronchoconstriction. The airway smooth muscle cells express β2-adrenergic receptors. Agonist binding to these receptors, such as by epinephrine or other β2-agonist drugs, results in smooth muscle relaxation.
Consequently, for acute bronchospasms many patients inhale short-acting β2-adrenergic agonists to prevent or reduce the severity of asthma attacks.
However, chronic administration of β2-adrenergic agonists has been demonstrated to lead to drug tolerance and reduced therapeutic effect on their continued administration. Reduced responsiveness, also known as tachyphylaxis or tolerance, results from a culmination of events, which include desensitization, sequestration, and down-regulation of receptors. Furthermore, there is also an increased hyperresponsiveness of the pulmonary airway in response to provocations such as allergens.
Epidemiological studies have demonstrated a positive correlation between the chronic use of short-acting β2-adrenergic agonists and asthma mortality. A large trial with the long-acting β2-adrenergic agonist, salmeterol, was stopped due to increased death rates. This underscores that, while short-term administration of β2-adrenergic agonists may be helpful to asthmatic patients and to patients with other diseases and conditions modulated by β2-adrenergic receptors, long-term administration of these agonists may be deleterious.
Conventional wisdom in the management of asthma and other diseases and conditions in which airway hyperresponsiveness and bronchoconstriction occur is that the administration of beta blockers, such as those that are frequently used in the treatment of cardiovascular conditions, are definitely contraindicated for asthmatic patients. In T. Clark & J. Rees, “Practical Management of Asthma” (2d ed, Martin Dunitz, 1996), it states: “These (β-blockers) often produce adverse effects when given to asthmatics, Treatment with beta blockers can also bring to light previously undiagnosed asthma. Fatal bronchoconstriction has been produced by a single dose of beta blockers. It is best to avoid all beta blockers in asthmatics.”
Therefore, there needs to be increased focus on the bronchoconstriction occurring in asthma. This can progress to status asthmaticus. More efficient and long-lasting therapeutic modalities that can reverse the bronchoconstriction and can bring about dilation of the airways are needed.
Consequently, there is a tremendous need for new therapeutic alternatives to β2-adrenergic agonist use in asthmatics and in patients suffering from other diseases and conditions modulated by β2-adrenergic receptors, particularly diseases affecting the respiratory system such as asthma.